The overall goal of this proposal is to develop technology for the next generation of PET imaging instruments. Improved PET imaging technology promises to aid and support cancer research, diagnosis, and treatment, which should lead to improved health care and patient management. The new PET instrument will be based on Lanthanum Bromide scintillators capable of excellent energy resolution, spatial resolution, and time-of-flight (TOP) measurement. The TOP technique requires an accurate measurement of the time difference between the two 511 keV gamma rays which result from the positron annihilation of the radioactive isotope (e.g. 18F) tagged to the PET tracer. The TOP information reduces the inherent noise in image reconstruction, thereby improving image quality. Our proposal seeks to evaluate performance of whole-body TOP PET instrumentation that will also fulfill the necessary requirements of a modern imaging instrument in terms of cost-effectiveness and reliability. The basic technology for TOP is already under development, and so we have emphasized in this proposal an evaluation each aspect of the system, initially to optimize the new technology,'but ultimately to further develop these techniques for improved performance. Investigations will encompass the scintillation detector performance, the calibrations of the detector and stabilization of processing electronics, data correction techniques, and the image reconstruction algorithm. Our goal is to develop detectors with coincidence tinning resolution of 200 ps or better, with electronics that are stable and capable of matching this timing accuracy. We will develop list-mode TOP image reconstruction with modeling of physical effects, and also investigate faster, rebinning methods of reconstruction. We will study the impact of TOP on accuracy of quantification, which is important for both clinical and research PET studies of cancer, and evaluate SNR improvements with TOP. We will use methodologies that are predictive of the human's ability to identify and quantify activity uptake in lesions, thereby guiding the utilization of TOP PET for the study of cancer.